The broad, long-term objective of this proposal for a cooperative drug discovery group is to meet the critical and urgent need for discovery of more effective and less toxic drugs and regimens for treatment of toxoplasmosis in AIDS patients. Toxoplasmosis has emerged as a major cause of morbidity in patients with AIDS. Drugs that have proven effective in treatment of toxoplasmosis in AIDS are extremely limited and those most commonly used are frequently associated with drug reactions sufficiently severe to preclude their further use in a given patient. Thus, there is a real need to discover and evaluate new treatment modalities for toxoplasmosis in AIDS patients. The specific aims of Project 1 are: a) to evaluate newer therapeutic agents/combinations for their activity against tachyzoites of T. gondii in vitro and in vivo. Mammalian cells in tissue culture and murine models of toxoplasmic encephalitis will be used in these studies; b) to use a newly developed technology to study therapeutic agents against the tissue cyst form and bradyzoites of T. gondii in vitro and in vivo. For this purpose mice with chronic central nervous system infection will be treated as well as cysts isolated from brains of chronically infected mice; c) to investigate the therapeutic potential of agents for toxoplasmosis. These studies will be performed in vitro in tissue culture as well as in in vivo in a model of systemic toxoplasmosis and models of toxoplasmic encephalitis; d) to examine drug-drug interactions of the effect of drugs being used to treat HIV infection on the in vitro and in vivo anti- toxoplasma effects of drugs being studied for treatment to toxoplasmosis in AIDS patients.